Microbiota-assisted therapy for systemic inflammatory arthritis: advances and mechanistic insights

Abstract

Research on the influence of gut microbiota on systemic inflammatory arthritis has exploded in the past decade. Gut microbiota changes may be a crucial regulatory component in systemic inflammatory arthritis. As a result of advancements in the field, microbiota-assisted therapy has evolved, but this discipline is still in its infancy. Consequently, we review the limitations of current systemic inflammatory arthritis treatment, analyze the connection between the microbiota and arthritis, and summarize the research progress of microbiota regulating systemic inflammatory arthritis and the further development aspects of microbiota-assisted therapy. Finally, the partial mechanisms of microbiota-assisted therapy of systemic inflammatory arthritis are being discussed. In general, this review summarizes the current progress, challenges, and prospects of microbiota-assisted therapy for systemic inflammatory arthritis and points out the direction for the development of microbiota-assisted therapy in the future.

Supplementary Information

The online version contains supplementary material available at 10.1007/s00018-022-04498-6.

Introduction

Microbes that colonize the human body are as least as 1.3–2.3 times more than our human cells and contain 100-fold more genes than the human genome [1], which provides the microbiome with greater adaptability and genetic variability [2–4]. However, the microbial population varies significantly among individuals, and it has not been understood how the microbiome of individuals changes and gradually affects human health. It has been identified that the changes of these microbiomes are associated with the interaction of the immunological, metabolic, secretory systems, and the illness onset and progression [5–8].

After more than a decade, the Human Microbiome Project has reached a major inflection point [9]. From attempting to characterize the microbiome changes associated with disease, to actively investigating the mechanism by which microbiota affect the disease, and to presently attempting to alter the microbial population as a novel therapeutic strategy [10]. In this context, microbiota-assisted therapies as alternatives are beginning to be known. Systemic inflammatory arthritis has been a research topic in the field of microbiota-assisted therapeutic development for a long time [11–14]. It is a type of chronic inflammatory disease, which mainly consists of rheumatoid arthritis and spondylarthritis (Fig. 1) [11], among which the most affected are rheumatoid arthritis (about 0.5–1% disease incidence), ankylosing spondylitis (about 0.3% disease incidence), and psoriatic arthritis (about 0.06–0.25% disease incidence) [15]. In the majority of patients, this type of disease results in immunological and inflammatory responses to antigens found in synovial tissue, cartilage, and bone, resulting in joint swelling, movement difficulties, and muscle soreness [11, 15]. Simultaneously, it will also disrupt and modify the function of synergistic immunity between the microbiota in the host and lymphoid tissue, thereby intensifying the inflammation [16, 17]. However, microbiome changes frequently occur before the onset of clinical symptoms [18, 19]. As a result, many researchers began to focus on the development of these diseases in an attempt to reverse the trend by treating patients with beneficial bacteria and their metabolites, which evolved into microbiota-assisted therapy [10].

Fig. 1.

Classification of systemic inflammatory arthritis

From the limitations of current systemic inflammatory arthritis treatment, this review discusses the relationship between the changes of gut microbiota in clinical and animal models and the development of systemic inflammatory arthritis, as well as microbiota-assisted early warning and the possibility of treating systemic inflammatory arthritis. Finally, the probable mechanism of microbiome intervention is discussed in relation to systemic inflammatory arthritis.

Conventional clinical medicine

The traditional medicine for systemic inflammatory arthritis

The traditional medicine for systemic inflammatory arthritis is divided into the following two types: non-steroidal anti-inflammatory drugs (NSAIDs) and slow-acting antirheumatic drugs (SAARDs). NSAIDs are the most classic fast-acting anti-inflammatory painkillers, which include aspirin, celecoxib, diclofenac, and fenoprofen [20]. The majority of NSAIDs are non-selective expression inhibitors of cyclooxygenase 1 (COX1) and cyclooxygenase 2 (COX2) to limit the formation of prostaglandins, prostacyclin, and thromboxanes [21]. As a result, it acts as an anti-inflammatory, reducing pain and swelling. However, COX1 inhibition may cause adverse effects such as nausea, stomach pain, ulcers, and gastrointestinal bleeding [22]. These adverse events, which include headaches, cognitive impairment, and allergic responses, frequently cause patients to discontinue treatment with NSAIDs [22]. The development of NSAIDs with selective COX2 inhibition, such as celecoxib, etodolac, meloxicam, and nabumetone, has significantly reduced the likelihood of gastrointestinal side-effects in recent years, but it may increase the risk of cardiovascular disease (Table S1) [23–25]. NSAIDs are frequently used in concert with omeprazole or misoprostol in clinical practice to protect the gastrointestinal tract and limit adverse effects, whereas this increases the burden on the liver and renal tissues [26]. On the other hand, though NSAIDs were frequently employed as first-line therapy for systemic inflammatory arthritis, they cannot completely cure inflammation and have no decisive influence on the immunopathological mechanism of arthritis. Therefore, SAARDs drugs represented by methotrexate must be added as early as possible. In comparison to NSAIDs, SAARDs are believed to be slow-acting, taking weeks or months to act. The purpose of SAARDs is to alleviate systemic inflammatory arthritis by delaying or avoiding joint deterioration and deformity progression [27]. While SAARDs do have several adverse effects, including diarrhea, nausea, and hepatorenal damage, however, most of them are reversible (Table S1).

The traditional hormone therapy for systemic inflammatory arthritis

Glucocorticoids, a regularly used immunosuppressive medication, can also be used to treat systemic inflammatory arthritis [28]. Glucocorticoids are a double-edged sword that can easily reduce joint swelling and stiffness while also causing notable side effects [28, 29]. As a result, they are only recommended to be used in small doses for a brief period when arthritis worsens or flares [30]. Methylprednisolone, prednisone, and triamcinolone are all typical examples of commonly used clinical glucocorticoids [31–33]. Weight gain, bone weakening, and immunosuppression are the most common adverse effects [34]. With the progression of the condition, it was customary to gradually decrease the dose of glucocorticoids in the clinic to minimize their negative effects.

Biological therapy for systemic inflammatory arthritis

Biological agents are also significant factors in the clinical treatment of systemic inflammatory arthritis. They are inhibitors of inflammatory factors and immune cells, including adalimumab, anakinra, tocilizumab, and secukinumab (Table S2) [35–38]. These biological agents can achieve a specific assault on inflammatory targets, as hence, they appear to work quickly and efficiently. In patients with low conventional pharmacological treatment effects, a high therapeutic benefit can also be achieved. Biological agents are much less likely to generate adverse effects, such as gastrointestinal pain and altered liver function, than those traditional drug treatments [39]. However, biological agents and their generic drugs are more expensive than conventional hormones and medicines. A typical report was that the entire medical expense associated with typical rheumatoid arthritis in the United States was around $12,509, whereas the entire directly medical cost associated with the use of biological agents was $36,053 [40]. Furthermore, while the overall efficacy rate of biological agents was higher than that of conventional drugs, it was not effective for all the patients and the risk of infection following the use of biological agents was significantly higher than that of traditional drugs [41]. These problems of biological agents often restrict their application to a certain degree.

Therefore, it could be observed that there were some problems with conventional clinical therapies, including medicine, hormone therapy, and biological therapy, such as significant side effects and costly care (Fig. 2). While some other issues remained, it nevertheless concurred that these conventional clinical therapies were the main therapies during the time of worsening or outbreak of systemic inflammatory arthritis. Under such a background, many researchers are also actively exploring the corresponding assistant therapy to improve the shortage of conventional treatment techniques. With the continuous growth of microbial technology and the continuous maturation of microbiome technology, the cost of high-throughput sequencing is declining, and the edible safety and function of probiotics are increasingly standardized. Microbiota-assisted therapy of systemic inflammatory arthritis has gradually become popular as a new concept. Microbiota-assisted therapy includes two aspects. On the one hand, changes in the microbiota may be monitored early in the development of systemic inflammatory arthritis to help assess the incidence of systemic inflammatory arthritis to minimize the occurrence risk and worsening progression of systemic inflammatory arthritis at the initial stage. On the other hand, after curbing the peak incidence of arthritis through routine clinical treatment, gradually reduce the use of biological agents, hormones, and even drugs, and stabilize the disease by taking probiotics or probiotic products to reduce the use of drugs, thereby, reducing the burden of drugs on the body.

Fig. 2.

Limitations of traditional clinical treatments and the need to develop microbiota-assisted therapy

Conventional clinical therapy has some drawbacks, such as significant side effects and high costs of care, such as medicine, hormone therapy, and biological therapy. The scarcity of conventional treatment options has sparked interest in complementary and alternative medicine. The cost of high-throughput sequencing is decreasing, and the edible safety and function of probiotics are increasingly standardized as microbial technology and microbiome technology continue to grow and mature. As a new idea, systemic inflammatory arthritis microbiota-assisted therapy is becoming increasingly popular.

Microbiota can be used as evidence for the identification of the risk of clinical and subclinical systemic inflammatory arthritis

The microbiota in healthy subjects is relatively stable but is also the first location to sense and react to undesirable changes if the body is stimulated by injury. The internal microbiota of individuals suffering from systemic inflammatory arthritis has been demonstrated to be disturbed in numerous studies [42–44]. This suggests that changes in the microbiota can be used to predict the onset of systemic inflammatory arthritis. As a result, the link between changes in the microbiota and systemic inflammatory arthritis will be further discussed, as well as the likelihood of it being an early warning sign.

Microbiota and rheumatoid arthritis

Rheumatoid arthritis (RA) is an autoimmune disease associated with HLA-class II [45]. Its symptoms include synovitis, articular cartilage damage, and bone loss. The possible pathogenesis is that T lymphocytes initiate inflammatory type degradation of synovial joints [46]. Researchers have focused on the genetic and environmental factors for rheumatoid arthritis. Genetically, the most significant risk factor for RA is the HLA-DRB1 susceptibility allele, which shares five amino acid sequences in the B1 chain [47]. The existence of these alleles greatly affects the positive occurrence of RA-specific autoantibodies, rheumatoid factor (RF), and anti-citrullinated protein antibodies (ACPAs) [48]. Along with genetic factors, many researchers investigated the environmental factors, such as smoking [49], hormones [50], microbiome [51], and infection [52]. In recent decades, there has been growing evidence that microbiota plays a role in the etiology of RA, as microbiota produce enzymes, chemicals, hormones, and vitamins that can interact with the metabolism of the host, accounting for roughly one-third of the recognizable metabolites in human blood [53]. These metabolites help maintain intestinal morphology, nutrient digestion and are critical components of metabolic function. In addition, they make significant contributions to immunological homeostasis, particularly mucosal barrier function [54]. A large number of symbiotic microorganisms colonize the mucosal surface of the oral and gastrointestinal tract, which not only affect the innate immunity but also shape the acquired immunity. The triggers of the immune system associated with arthritis may be associated with these symbiotic microorganisms in the oral [55] and gastrointestinal mucosa [18]. It is believed that the transition from symbiosis to non-symbiosis is the key transition of the microbial community from a stable state to a disease state. At present, researches on the role of microbiota in the occurrence and development of RA mainly focused on exploring the disorder of oral and gut microbiota in patients with RA, which leads to local immune disorders and inflammation, and then induces the immune response of distal organs, resulting in systemic inflammation. The alterations in the gut microbiota and cytokines in collagen-induced arthritis (CIA) mouse model were investigated [56], and it was shown that the mucosal alterations of CIA mice were related to the imbalance of microbiota, which could stimulate mucosal Th₁₇ immune response and lead to the phenomenon of autoimmunity caused by immune cell expansion and cyclin. Similarly, another study demonstrated that when feces from RA patients were inoculated into SKG mice, intestinal T cells could be activated, resulting in arthritis [57]. Li and colleagues collected feces from 205 RA patients and 199 healthy controls [42], and 16S sequencing results revealed that patients with RA had a considerably different gut microbiota compared with healthy subjects, and the richness and diversity of their gut microbiota were impaired. Hence, it was postulated that gut microbiota in patients with RA may regulate the immune system and the pathogenesis of RA through lymphocyte subsets and cytokines. From those findings, it may be concluded that microbiota has a role in every facet of the immunological regulation of RA. Although a decline in intestinal microbial diversity is a frequent aspect of disease incidence, changes in specific microbial species associated with RA may be more etiologically significant. The development of microbiota-assisted therapy and research on the specific changes of microorganisms in arthritis patients may be one of the most exciting prospects for the prevention or treatment of RA. Therefore, the alterations in certain species of microorganisms associated with RA, as well as relevant insights from oral and intestinal perspectives will be further discussed.

The role of Porphyromonas gingivalis in rheumatoid arthritis

The oral cavity, being the beginning of the digestive tract, includes a significant number of microorganisms that link to human health and disease [58]. Although the oral cavity has a robust line of defense against low-grade microbial invasions, such as oral squamous epithelium and respiratory mucosal epithelium, there were weak links in the gingival mucosa, especially those near the periodontal tissue [59]. Periodontal tissue is a perfect place for long-term symbiosis and settlement of microorganisms and is also an important part of oral mucosal immune stimulation [55]. In recent decades, periodontal disease and RA have been thought to be linked, but the exact linkage between them has only been discovered recently when researchers focused on Porphyromonas gingivalis (Porp. gingivalis), an anaerobic gram-negative bacterium belonging to the Bacteroidetes phylum [57]. It is a natural part of the human oral microbiota and one of the main causes of gum disease. Porp. gingivalis can change the periodontal microbiome negatively and jointly stimulate the occurrence of destructive inflammation [60]. Anti-citrullinated protein antibody levels in the blood have been associated with the severity of RA in epidemiological studies [61]. The citrullination of the protein is accomplished by the peptidyl arginine deiminase (PAD) enzyme. PAD enzyme can catalyze the conversion of arginine to citrulline on the peptide group to maintain the normal physiological activity of the human body [62]. Moreover, citrullination catalyzed by the PAD enzyme also occurs in RA, a pathological systemic inflammatory arthropathy, and is related to the decrease of immune tolerance of citrullinated protein [63]. Interestingly, Porp. gingivalis can produce PAD enzyme as well and have the same activity as human PAD enzyme [64]. However, the gene encoding Porp. gingivalis peptidyl arginine deiminase (PPAD) is not homologous to that of human PAD (Fig. 3)[64]. Heretofore, only three kinds of bacteria, Porp. gingivalis, Porp. gulae, and Porp. loveana were reported to produce PAD enzyme, and the latter two only exist in animals [65]. Porp. gingivalis can secrete gingipain family proteases; one is arginine-specific cysteine protease (Rgp, conclude RgpA and RgpB), and the other is lysine-specific cysteine protease (Kgp) [66]. These proteases are involved in periodontal invasion and destruction of important matrix components such as tight junction protein JAM1 [67]. They can cleave the host protein, exposing the arginine residue at the end of the peptide, which is then citrullinated by PPAD and targeted by the immune system, resulting in positive RA biomarker antibody ACPA (Fig. 3) [68, 69]. Additionally, they can interfere with the host immune response by cleaving T cell surface proteins like CD4, CD8, IFN- γ, IL-6, IL-8, and other cytokines, resulting in the occurrence of RA and the aggravation of inflammation [70]. It was found that Porp. gingivalis can activate an alternative TLR2-Mal-PI3K pathway while disarming a host-protective TLR2-MyD88 route via proteasomal degradation of MyD88. This alternative TLR2-Mal-PI3K pathway inhibits phagocytosis, protects otherwise susceptible bacteria, and promotes dysbiosis inflammation in vivo (Fig. 3) [71]. Another report also suggested that Prop. gingivalis may play an important role in RA patients [72]. Oral Porp. gingivalis levels were found to be five times higher in RA patients with RF-IgA levels higher than 75 IU/ml and increased sixfold in patients with DAS-28 scores > 3.2. Similarly, another research group found that the detection rate of Porp. gingivalis DNA in the synovial fluid of the RA group was 15.7% higher than that of controls (3.5%) [73]. The RA patients with DNA in oral plaque and synovial fluid containing Porp. gingivalis were significantly higher than those in the healthy subjects (11.9% vs. 0.9%). These data suggest that Porp. gingivalis plays an important role in the pathogenesis of arthritis with a positive correlation. By tracking variations in Porp. gingivalis in different locations of the body, it may be possible to predict the onset of RA.

Fig. 3.

The role of Porphyromonas gingivalis and Prevotella in rheumatoid arthritis (RA) progress

The role of Prevotella in rheumatoid arthritis

Prevotella is an anaerobic gram-negative bacterium, which belongs to Bacteroides [74]. Prevotella is a symbiotic bacterium that dwells on the mucosal surface and the digestive tract, including the oral and gastrointestinal tract, as well as the lungs and genitourinary system [75]. Prevotella plays a role mainly through intestinal mucosal immunity. Prevotella community in the human is related to diet habits in healthy people, and it is somewhat greater in the oriental population, associated with a significant proportion of the plant-derived diet, but somewhat lower in the western population, associated with a higher intake of animal protein [76]. To some extent, the existence of Prevotella is similar to a double-edged sword. On the one hand, Prevotella possesses specific probiotic features that may enhance glucose metabolism when probiotics are consumed [77]; on the other hand, Prevotella plays a critical role in a variety of immunological and inflammatory-mediated disorders, including RA. A recent study found a significant increase in a variety of Prevotella species in patients with RA, such as Prev. denticola, Prev. marshii, Prev. disiens, Prev.corporis, and Prev. amnii, in a metagenomic sequence of 82 patients with RA and 42 healthy people in Japan [78]. However, more literature reported that Prev. copri may serve a more important role in RA. It was discovered that in the gut microbiota of early RA patients Prev. copri dominated [79]. After the fecal microbiota of RA patients was transplanted into SKG mice, an increase in the number of intestinal IL-17 cells was found and the recipient animals developed severe arthritis. Prev. copri can cause bone marrow-derived dendritic cells to activate immature Th cells and increase the level of IL-17 up to five times, which means that Prev. copri has the potential ability to promote Th17, which can further promote the occurrence and development of RA when it occurs in the gastrointestinal tract. From a molecular perspective, the incidence of RA is associated with the molecular binding of HLA-BR. Another study used proteomic techniques to detect the peptides presented to HLA-BR in the synovium or peripheral blood mononuclear cells [80] and identified two autoantigens, N-Acetylglucosamne-6-Sulfatas (GNS) and filamin A (FLNA). Among them, GNS and FLNA are highly expressed in the synovium, and the level of GNS is associated with the RA-specific antibody ACPA. The GNS and FLNA expressed by Prevotella had significant sequence homology with the epitopes of GNS and FLNA presented in humans to HLA-DR. Thus, HLA-DR molecules encoded by shared epitope alleles strongly bind to two kinds of biological peptides produced by themselves and those produced by microorganisms, thus leading to the deterioration of RA (Fig. 3) [81]. It is speculated that there may be a threshold for Prevotella to participate in the induction of RA. Under normal conditions, Prevotella may have different abundances in different regions due to different diet habits, but they may all be under this threshold. In this case, the interaction between Prevotella and the immune system is balanced, the immune regulation can be controlled, and they are partial probiotics. However, when its reproduction exceeds this threshold or breaks through the mucosal barrier to produce displacement, the role of Prevotella may gradually change into aggravating the immune response and promoting the development of inflammatory diseases. Therefore, this will occur in the early stage of the onset of RA; the abundance of Prevotella in the feces of patients is higher than that of healthy controls, which means that Prevotella, especially Prev. copri can be included in the early diagnosis of RA as a risk factor in the early stage of disease development.

Porphyromonas gingivalis can produce PAD enzyme and has the same activity as the human PAD enzyme. Furthermore, citrullination catalyzed by the PAD enzyme occurs in RA and is linked to a decrease in immune tolerance of citrullinated protein. Porphyromonas gingivalis can also secrete gingipain family proteases, including arginine-specific cysteine protease (Rgp) and lysine-specific cysteine protease (Kgp). These proteases are involved in periodontal invasion and the destruction of important matrix components, cleaving the host protein, exposing the arginine residue at the end of the peptide, which is then citrullinated by PPAD and targeted by the immune system, resulting in positive RA biomarker antibody ACPA. Porphyromonas gingivalis can activate an alternative TLR2-Mal-PI3K pathway while disarming a host-protective TLR2-MyD88 route via proteasomal degradation of MyD88. In vivo, this alternative TLR2-Mal-PI3K pathway inhibits phagocytosis and promotes dysbiosis inflammation. The GNS and FLNA expressed by Prevotella shared significant sequence homology with GNS and FLNA epitopes presented to HLA-DR in humans. Thus, HLA-DR molecules encoded by shared epitope alleles bind strongly to two types of biological peptides produced by themselves and those produced by microorganisms and then causing RA to worsen. RA, rheumatoid arthritis. PPAD, Porphyromonas gingivalis peptidyl arginine deiminase; Rgp, arginine-specific cysteine protease; Kgp, lysine-specific cysteine protease; TLR, Toll-like receptors; GNS, N-acetylglucosamine-6-sulfase; FLNA, filamin A; ACPA, anti-citrullinated peptide antibodies; HLA-DR, human leukocyte antigen DR.

Microbiota and spondylarthritis

Spondyloarthritis (SpA) is a group of chronic inflammatory rheumatic diseases, mainly including ankylosing spondylitis (AS), psoriasis arthritis (PsA), reactive arthritis (ReA), and enteropathy arthritis (EA) [82]. Among them, most SpA patients were diagnosed with AS or PsA clinical phenotype, and only a small number of patients were diagnosed with other SpA. The occurrence of SpA is affected by genetic factors, in which the MHC class I allele is the most important, particularly HLA-B27 [83]. Since HLA-B27 was firstly reported its association with SpA in 1973, 25 different HLA-B27 alleles, known as subtypes (B*2701-B*2725) which can encode 23 protein products, have been found [84]. Among them, B*2705 is called “ancestor” and is also one of the subtypes closely related to SpA [85]. Currently, the occurrence of SpA is mainly determined by antibody detection combined with imaging observation. SpA delay diagnosis remains a major problem widely in the world. For example, the average time interval between the beginning of symptoms and diagnosis in AS was up to 8–10 years due to the insidious progression [13], which demonstrated that the current clinical detection methods may not be able to diagnose the disease in the early stage, resulting in the delay of confirmation of the disease. Hence, it is worthy to explore other auxiliary diagnostic methods to help determine the existing diagnostic methods. Interestingly, it was found that intestinal inflammation is an important factor leading to SpA. Approximately 30% of IBD patients develop SpA and 10–15% of SpA patients have a history of IBD, and 60% of patients without gastrointestinal disease showed signs of mild intestinal inflammation [43, 86, 87]. Although the links of intestinal inflammation to the onset of SpA remain unclear, one of the most important factors in gut microbiota, which plays an important role in this axis of intestinal arthritis. Some studies have shown that feeding HLA-B27 transgenic rats in an aseptic environment will not induce SpA or even arthritis, but after the introduction of the new gut microbiota, arthritis and intestinal inflammation began to appear [88, 89]. Similar results were found in human trials. The gut microbiota of HLA-B27-positive patients was considerably different from that of healthy individuals, implying that gut microbiota may be an important driver of SpA [43]. One hypothesis is that HLA-B27 presents specific peptides to CD8⁺T cells resulting in a pathogenic immune response, as gut microbiota produces a wide variety and a large number of microbial peptides which may activate CD8⁺T cells. Other reports provided the basis for this hypothesis that intestinal CD8⁺T cell populations were enlarged in the peripheral blood and synovium of SpA and AS patients through the observation of immunity cells [90, 91]. The role of the microbiota in different animals’ models seems to be different. Prevotella, Clostridium, and Brucella played important roles in Lewis rats, while members of Akkermania and Lactobacillus played a major role in Fischer rats [86, 92]. Uchiyama and colleagues summarized that there was a higher relative abundance of Lachnospiraceae, Ruminococcaceae, Rikenellaceae, Porphyromonadaceae, and Bacteroidaceae, and lower relative abundance of Veillonellaceae and Prevotellaceae in the intestines of patients with SpA [93]. From the influence of gut microbiota on RA and SpA, one or several specific microorganisms in RA play important roles in the pathogenesis of RA, while in SpA, the transmission of inflammation, the activation of related effector cells, and the cooperation of multiple gut microbiota may play a major role. At present, the research on the gut microbiota of SpA is not as mature as that of RA and with the continuous evolution of microbial detection methods and the continuous progress of microbiota-assisted therapy, appropriate clues from the changes of this microbiota to predict the occurrence of SpA and its related diseases may be found.

The role of microbiota in ankylosing spondylitis

Ankylosing spondylitis (AS) is a kind of SpA characterized by inflammation of the sacroiliac joint and spinal attachment point, and there is no significant increase in rheumatoid factor [93]. Severe AS patients may exhibit spine abnormalities, spinal ankylosis, and bamboo-like alterations in the spinal column [94]. AS is most frequently diagnosed in young people, with an average age of onset of 18–30 years and a male to female prevalence ratio of approximately 2:1 ~ 1.1:1 [95]. Klebsiella pneumoniae is the first microbe found to be associated with AS, and its effect on humans may precede the changes in HLA-B27 [96]. Kleb. pneumoniae usually exists as a part of commensal microorganisms, but sometimes presents as an opportunistic pathogen [97]. In 1976, the detection rate of Kleb. pneumoniae in the feces of patients with AS accounted for 76%, while that in the control group was less than 30% [98]. Seager and colleagues prepared antisera against various Klebsiella isolates from rabbit serum and tested the toxicity of those antisera to lymphocytes in patients with AS and control [99], and the results showed that some Klebsiella antisera could dissolve lymphocytes in HLA-B27-positive AS patients, but not in HLA-B27-negative AS patients. Interestingly, the cytotoxicity of antiserum could only be cleared by HLA-B27-positive AS patients, not by HLA-B27-positive or negative control subjects, suggesting that Klebsiella may play an important role in the occurrence and development of AS. Some studies have shown that the HLA-B27 molecule possessed six consecutive amino acids as being the same as the nitrogenase reductase molecule of Kleb. pneumoniae, which was Gln-Thr-Asp-Arg-Glu-Asp [100]. Therefore, Kleb. pneumoniae may be involved in the pathogenesis of AS through HLA-B27 molecular simulation (Fig. 4). However, these conclusions are mainly based on serological tests and have not been universally accepted. Given the leading role of Kleb. pneumoniae in AS, some researchers have different opinions in recent years. Stone et al. recruited 25 families with two or more individuals affected with AS, in which 57 were affected by AS and 37 were normal [101], and their analysis on family members with and without familial AS involvement showed no significant difference in cellular and humoral responses among Kleb. pneumoniae, Salmonella typhimurium, Yersinia enterocolitica, and Chlamydia trachomatis. In addition, Kleb. pneumoniae did not show a major immune response in the affected individuals, and there was no supporting evidence that Kleb. pneumoniae played a causal role in familial AS. Although Klebsiella is controversial in the pathogenesis of AS, researchers have also observed that some bacteria play an important role in the occurrence and development of AS in recent years. Liu et al. extracted DNA from the feces of 10 AS patients and 12 healthy controls and by sequencing the 16S rRNA, they found that the relative abundance of Bacteroides in the gastrointestinal tract of AS patients were lower, but the relative abundance of Firmicutes and Verrucomicrobia were higher (Fig. 4). The relationship between gut microbiota and CRP and ESR was investigated and found that the abundance of Firmicutes and Verrucomicrobia was positively correlated with the contents of ESR and CRP, while the abundance of Bacteroides was negatively correlated with the contents of ESR and CRP [102]. Another study found more Bacteroides coprophilus, Parabacteroides distasouis, Eubacterium siraeum, Acidaminococcus fermentans, and Prev. copri in the feces of AS patients through metagenomics, and the related pathway analysis showed that oxidative phosphorylation, lipopolysaccharide biosynthesis, and glycosaminoglycan degradation were increased in gut microbiota [103]. Combined with those existing results, the effects of gut microbiota on AS patients may not play a major role by one bacterial species, but by the cooperation of multiple microbiotas. Indeed, a large part of the result is that the development of microbial technology is not yet mature to the whole state, and the research on the pathogenesis of AS is not as mature as RA. Therefore, the research on characteristic bacteria remains on the change of microbiota, but exactly which bacterial species play the dominant or crucial role remains to be further investigated and exploited for microbiota-assisted therapy.

Fig. 4.

The role of microbiota in ankylosing spondylitis (AS) and psoriatic arthritis (PsA)

The role of microbiota in psoriatic and psoriatic arthritis

Psoriatic arthritis (PsA) is an important concomitant disease of psoriasis (PS). Patients present with a psoriatic rash that is accompanied by systemic joint and soft tissue pain, edema, stiffness, and dyskinesia [104]. In 84% of psoriasis patients, skin psoriasis precedes the start of PsA (Fig. 4) [105]. At present, it is known that the changes of gut microbiota are involved in the pathogenesis of PS and PsA. Shapiro et al. recruited 46 volunteers to explore the relationship between gut microbiota and PS[44], among which 52% (n = 24) of people suffered from PS. Firmicutes and Acinobacteria were considerably increased in the PS group compared to control; at the genus level, Ruminoccocus, Coprococcus, Collinsella, and Faeclibacterium were increased significantly, while Prevotella and Bifidobacterium were significantly lower. Furthermore, alterations in Firmicutes were associated with the development of PS, including increasing Faeclibacterium and reducing Oscillibacter and Roseburia [106]. Gut microbiota of 16 PsA patients, 15 PS patients, and 17 healthy controls were compared and analyzed [107], and it was found that patients with PS and PsA were both lower in the number of Coprococcus, while only PsA patients showed significant decreases in Akkermansia, Ruminococcus, and Pseudobutyrivibrio. The main function of Coprococcus in the gastrointestinal tract is to ferment carbohydrates, which can enhance gastrointestinal function and reduce the level of inflammation [108]. Besides, the decrease of Coprococcus in patients with PS and PsA indicated that the gastrointestinal microenvironment began to alter, which promoted the development of disease. Hence, Coprococcus may play a major role in the occurrence of rash in PS and PsA (Fig. 4). The main role of Ruminococcus in the gastrointestinal tract is to produce short-chain fatty acids (SCFAs), particularly formic acid and acetic acid [109]. As bacteria that produce SCFAs are generally beneficial, it was speculated that the mutual evolution or transformation between PS and PsA may be caused by the change of gut microbiota. The relative abundance of changes of Ruminococcus from high to low may be an important signal of the transformation from PS to PsA (Fig. 4). However, there are few studies on PsA at the present, and it is not clear what causes the gut microbiota to transform from PS to PsA, and which species or strains in Ruminococcus play a major role. Microbiota-assisted therapy in the early stage of PS may be beneficial and detecting the changes of gut microbiota to prevent or delay the occurrence of PsA could be an introduced strategy for the future.

Changes in the microbiome are linked to the pathophysiology of AS and PsA. Klebsiella pneumoniae may play a role in the pathogenesis of AS via HLA-B27 molecular simulation. However, the relative abundance of Bacteroides in the gastrointestinal tracts of AS patients was lower, while Firmicutes and Verrucomicrobia were more abundant. The effects of gut microbiota on AS patients may be mediated not by a single bacterial species, but by the collaboration of multiple microbiotas. Skin psoriasis occurs in 84 percent of psoriasis patients before the onset of PsA. Patients with PS and PsA had lower levels of Coprococcus, but only PsA patients had lower levels of Akkermansia, Ruminococcus, and Pseudobutyrivibrio. The decrease in Coprococcus in patients with PS and PsA indicated that the gastrointestinal microenvironment became disordered, which aided in disease development. Ruminococcus’ primary function in the gastrointestinal tract is to produce SCFAs, specifically formic acid and acetic acid. The mutual evolution or transformation of PS-to-PsA may be caused by a change with Ruminococcus' relative abundance. AS, ankylosing spondylitis; PS, psoriasis; PsA, psoriatic arthritis; SCFAs, short-chain fatty acids; HLA-B27, human leukocyte antigen B27.

Possible mechanisms of microbiota-assisted therapy on systemic inflammatory arthritis

Probiotics, ROS, and redox homeostasis

Reactive oxygen species (ROS) are a group of bioactive molecules that affect the process of human aging and disease, by affecting metabolism, cytotoxicity, and stimulation of external conditions. It mainly includes O2⁻, H₂O₂, and ·OH [110]. The effect of ROS on humans is a double-edged sword [111], which can not only act as a signal molecule to participate in signal transduction [112] but also lead to damage of oxidation defense ability and loss of redox homeostasis [113]. ROS can also activate or produce damage-related molecular substances or autoantigens, which can initiate innate or adaptive immunity, thus affecting the course and development of systemic inflammatory arthritis [114, 115]. In PsA, oxidative stress can be observed in skin cells, plasma, and blood cells, including granulocytes and lymphocytes [116]. Similar to PsA, oxidative stress can trigger RA, and participate in its pathogenesis, and even promote the occurrence of muscle weakness caused by RA [117]. There are a large number of neutrophils in the synovium of patients with RA [118], and these neutrophils produce a large amount of ROS, and hence, high levels of ROS and hydroxyl radicals in the synovium of patients with RA could be detected [119]. Furthermore, the levels of ROS and hydroxyl radicals are related to DAS28 and the evaluation standard of RA [120, 121]. In addition to affecting neutrophils, ROS can stimulate macrophages in the synovium of RA patients to differentiate into pro-inflammatory phenotype M1, and then produce pro-inflammatory cytokines such as TNF-α, IL-6, MCP-1, and growth factors, which lead to inflammation, cartilage degradation, and bone erosion, and aggravate the development of RA [122].

Additionally, ROS can activate the transcription factors (Fig. 5). Oxidative stress-dependent activation of transcription factors can aggravate inflammation and activate immune cells, thus regulating the biosynthesis of antioxidant proteins and pro-inflammatory factors. As the core transcription factor of the Keap1-Nrf2-ARE pathway, Nrf2 plays an important role in the pathogenesis of systemic inflammatory arthritis [123]. The increase of ROS in joints can also activate the host defense, and activate the expression of protein lipase C (plC), which in turn activates the phosphatidylinositol 3-kinase (PI3K) pathway [124], then phosphorylates Nrf2 and stimulates the release of Keap1, and makes it move toward the nucleus [125], and binding to ARE activates the transcription of downstream genes and then translates a series of related proteins to play physiological functions [126]. Nrf2 is not only sensitive to the redox state to regulate its Keap1-Nrf2-ARE pathway, but also can respond to inflammatory stimuli and regulate the changes of NF-κB, MAPK, and other related pathways and genes [127]. NF-κB/NLRP3 pathway can regulate the activation and release of cytokines and inflammatory bodies [128]. Abnormal upregulation of NF-κB and NLRP3 can lead to the formation of inflammatory complexes, activate macrophages, and promote various pro-inflammatory factors, such as IL-6 and IL-1β [129]. The abnormal expression upregulation of those genes was also one of the important mechanisms of inflammatory arthritis such as RA, AS, and PsA. Nrf2 is an effective inhibitor of NF-κB and NLRP3 [130]. Clinically, Nrf2 regulators are often used to alleviate the occurrence of autoimmune or inflammatory diseases caused by NF-κB and NLRP3 [131]. Another transcription factor involved in cell-mediated inflammation is AP-1, whose activation is mainly achieved by phosphorylation of the related gene JNK in the MAPK pathway [132]. Nrf2 can block the transduction mechanism of JNK2 or AP-1 to reduce the expression of COX-2 [133]. Meanwhile, Nrf2 can also up-regulate the expression of CD36 and HO-1 in macrophages, thus dissolving and eliminating inflammation [134] and Nrf2 can also inhibit the pro-inflammatory response related to Th1 and Th17 cells, activate a variety of anti-inflammatory responses in Treg, Th2, and Breg cells, thus regulating the immune system [135].

Fig. 5.

Probiotics can regulate inflammation caused by ROS disorder in the body

The imbalance of ROS will first activate the body's defense system. It can stimulate the expression of plC, which in turn activates the PI3K pathway, phosphorylates Nrf2, and stimulates the release of Keap1, causing it to move toward the nucleus, and binding to ARE activates the transcription of downstream genes and translates a series of related proteins to perform physiological functions. ROS will inhibit the activation of the Keap1-Nrf2-ARE pathway when the body's defense system is insufficient to resist the damage caused by ROS. Furthermore, ROS can increase the number of neutrophils in the joint, and it not only promotes macrophage differentiation into the pro-inflammatory M1 phenotype, but it also promotes NF-κB entry nuclear and up-regulation of inflammatory factor expression. However, taking probiotics can help to regulate ROS in the body and reduce the damage caused by an imbalance in ROS. ROS, reactive oxygen species; plC, protein lipase C; PI3K, phosphatidylinositol 3-kinase; Nrf2, nuclear factor E2-related factor 2; ARE, antioxidant responsive element; Keap1, kelch-like ECH-associated protein-1; NF-κB, nuclear factor kappa-B.

At present, many studies were performed on probiotics to alleviate ROS and oxidative stress. Macarro and colleagues evaluated a probiotic product containing three strains (Bif.longum CECT 7347 and Lactobacillus casei CECT9104, Lact. rhamnosus CECT8361) and found that probiotics significantly improved the redox homeostasis in subjects and reduced the levels of oxidation products such as malondialdehyde [136]. Pediococcus pentosaceus ZJUAF-4 could significantly increase the expression levels of Nrf2 and HO-1 in the jejunum and decrease the level of ROS in the jejunum of mice, thus protecting mice from oxidative stress [137]. Monteros and colleagues studied the relieving effects of Lact. casei CRL431 and Lact.parasitum CNCMI-1518 on intestinal inflammation induced by indomethacin (namely NSAIDs). Administration of probiotics in indomethacin-induced intestinal inflammation reduced the production of ROS and pro-inflammatory factors by peritoneal macrophages [138]. In summary, although there are no reports on probiotics directly acting on arthritis patients to improve oxidative stress, we postulate that ROS may be a target for probiotics to alleviate the local or systemic redox imbalance caused by systemic inflammatory arthritis.

Probiotic’s regulation of short-chain fatty acids and receptors

SCFAs are direct products from fiber and carbohydrate fermentation by probiotics and gut microbiota. SCFAs mainly include acetic acid, propionic acid, isobutyric acid, butyric acid, isovaleric acid, valeric acid, and the proportion of these SCFAs in the intestine varies. In the colon, acetic acid is the most abundant SCFA, at 60%, followed by propionic acid (~ 25%), butyric acid, and other SCFAs account for the remainder [139]. SCFA concentrations are highest in the cecum and colon, and the colon is the main absorption organ of SCFAs. Approximately 95% of SCFAs are absorbed in the colon [140]. Among them, acetic acid can promote the production and be transformed into other SCFAs through biochemical and/ or respiratory pathways, particularly butyric acid, which is the preferred energy source for colonic cells and has a far-reaching effect on maintaining the homeostasis and function of the intestinal epithelium [141].

SCFAs play important roles in shaping the immune system and regulating the inflammatory response. The changes of T cells provided the conditions for regulating the balance between pro-inflammatory response and anti-inflammatory response [142]. The effect of SCFAs on the function of the immune and metabolic systems may be related to T cells [143]. In collagen-induced arthritis (CIA) mice, SCFAs supplementation can improve the damaged function of Treg cells [144]. SCFAs can induce the differentiation of CD4⁺Foxp3⁺Treg cells [145] in vitro and it was found that administration of Bif. adolescence before modeling in CIA rats can prevent and relieve arthritis symptoms, balance the pro-inflammatory and anti-inflammatory responses, and maintain the concentration of SCFAs in feces [146]. Butyric acid can inhibit arthritis in CIA mice by inhibiting the expression of inflammatory factors [147], by mediating the differentiation of CD4⁺ T cells into Treg cells, resulting in the production of anti-inflammatory factor IL-10, and then affecting the function of Th17 cells. In addition, acetic acid can increase the ability of memory CD8⁺T cells to produce IFN- γ [148]. Once the SCFAs produced by microorganisms are absorbed by T cells, they will enhance the expression of mTOR-related genes and proteins in the cytoplasm [149] and increase the conversion of pyruvate to acetyl-CoA (AcCoA) in the tricarboxylic acid (TCA) cycle (Fig. 6) [150]. The acetyl component of SCFAs can also be linked to the cellular pool of CoA by acetyl-CoA synthase and other enzymes. [148]. ATP citrate lyase can convert the excess citrate released into the cytoplasm formed in the TCA cycle back to AcCoA and transferred to the nucleus [151]. AcCoA in the nucleus together with histone acetyltransferases (HAT) is used for the regulation of pro-inflammatory and anti-inflammatory factors [152]. In addition, the decrease or blockage of ATP citrate lyase activity will lead to a decrease in the levels of IL-10 and IFN-γ in cells [153]. To sum up, SCFAs produced by microorganisms can act as the precursor molecules of acetyl-CoA, participate in the metabolic process of T cells, thus regulate the expression of inflammatory factors, and then affect the development of inflammatory arthritis.

Fig. 6.

Microbiota regulates inflammation by regulating short-chain fatty acids (SCFAs)

Once microorganism-produced SCFAs are absorbed by T cells, they enhance the expression of mTOR-related genes and proteins in the cytoplasm and increase pyruvate to acetyl-CoA (AcCoA) conversion in the TCA cycle. By using acetyl-CoA synthase and other enzymes, the acetyl of SCFAs can be linked to the cellular pool of CoA. ATP citrate lyase can convert excess citrate formed by acetyl-CoA in the TCA cycle back to AcCoA and transfer it to the nucleus. AcCoA is used in the nucleus in conjunction with HAT to regulate pro-inflammatory and anti-inflammatory factors. Additionally, inhibition or inhibition of ATP citrate lyase activity results in a decrease in IL-10 and IFN-γ levels in cells. SCFAs, short-chain fatty acids; AcCoA, acetyl-CoA; TCA, tricarboxylic acid; HAT, histone acetyltransferases.

SCFAs can also regulate the immune system through G-protein coupled receptors. The SCFAs in the gastrointestinal tract can pass through the intestinal epithelium and interact with the surface molecules on the immune cells in the lamina propria [154]. G protein-coupled receptor (GPR) is a general term for membrane protein receptor in this surface molecule [155]. At present, three GPRs are sensitive to SCFAs and play a regulatory role, which is known as SCFAs receptors, namely GPR41 (FFA3R), GPR43 (FFA2R), and GPR109A (HCAR2). The affinity of GPR41 and GPR43 to different SCFAs differs. The affinity of SCFAs to GPR41 is pentanoic = propionic = butyric > acetic > formic, while that of GPR43 is acetic = propionic = butyric > pentanoic > formic [156]. GPR109A endogenous ligands are β-hydroxybutyric acid (BHBA). Nicotinic acid and butyric acid as exogenous ligands can also activate GPR109A [157]. The interaction between SCFAs and the receptors may control the occurrence and development of inflammation by regulating inflammation-related pathways such as NF-κB and MAPK, then affect the release of pro-inflammatory mediators such as iNOS, COX2, TNF-α, IL-1β, and IL-6. As a result, the SCFAs receptor is gaining increasing attention as a therapeutic target for inflammatory disorders [158]. However, there are currently divergent views regarding whether activation of the SCFAs receptor is protective or harmful. Smith et al. suggested that knocking out GPR43 increases the severity of colitis [159]. A similar result was found that SCFAs stimulation to GPR43 is necessary to address some inflammatory responses. Moreover, GPR109A is essential for butyric acid-mediated protection in the intestine, and mice lacking this molecule are more likely to induce inflammation [160]. In contrast, GRP41 and GRP43, which activate intestinal epithelium, promote inflammation in mice. For those seemingly contradictory results, SCFAs receptors should be essential for the anti-inflammatory effect [158]. However, there may be a threshold for the activated signal. When the signal is activated but below the threshold, these receptors actively play an anti-inflammatory effect, and once the signal activation is higher than the threshold, their efficacy may change from anti-inflammatory to pro-inflammatory. However, it is not clear whether there is a smooth transition of this transition, and further research on its mechanism needs to be carried out.

Probiotics help repair the intestinal barrier

The intestinal barrier is the most intimate part of the interaction between gut microbiota and the host [161]. In a broad sense, the intestinal barrier is mainly composed of the internal mucous layer, intestinal epithelial cells, immune cells in lamina propria, and intestinal-associated lymphocytes [161]. Among them, the internal mucus layer is the first line of defense in the intestinal barrier; if the internal mucus layer is destroyed, the intestinal epithelial cell layer will maintain its impermeability to pathogens and toxins through complete tight junctions (TJs) [162]. In recent years, the results from patients with systemic inflammatory arthritis and animal models have shown that the pathogenesis of arthritis is related to the change of mucosal and intestinal permeability [163, 164]. Therefore, the effect of gut microbiota on systemic inflammatory arthritis particularly on the TJs of intestinal epithelial cells, and the possible assistant therapy mechanism of probiotics to enhance TJs will be discussed.

Systemic inflammatory arthritis can lead to the damage of TJs in the gastrointestinal tract and promote the development of the disease. TJs proteins are located at the junction of the parietal mode and the lateral membrane of intestinal epithelial cells and are mainly composed of some transmembrane proteins, such as Occludin, Claudins, and JAMs [165]. Those transmembrane proteins can interact with the surface proteins of adjacent cells, and those interactions may be homologous (such as Claudin-1 and Claudin-1), or heterologous (such as Claudin-3 and Claudin-1) (Fig. 7) [166, 167]. The expression of TJs protein is regulated by many factors, including epithelial apoptosis, cytokines, and immune cells. Tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ) can destroy Claudin and Occludin, then increase the intestinal permeability by inhibiting the expression of TJs [168]. When the intestinal barrier is damaged, bacterial metabolites, such as LPS, can enter into plasma with the change of intestinal permeability, which leads to the aggravation of inflammatory response in various tissues [169]. The typing of HLA will lead to different susceptibility to arthritis in mice, and arthritis-prone mice show higher intestinal permeability [170]. When the intestinal barrier is damaged, microorganisms that can translocate to epithelial cells activate self-reactive B and/ or T cells through antigen recognition, and these activated immune cells can migrate to the surrounding tissue to cause inflammation. In addition, as a kind of enterotoxin secreted by intestinal epithelial cells stimulated by diet or microorganisms, Zonulin is the main regulator of intestinal tight junction protein and intestinal barrier [171], and it was shown that the level of Zonulin increased in RA patients [172]. Moreover, CIA mice displayed an increase in intestinal permeability and serum Zonulin levels [163]. By inhibiting Zonulin, poor intestinal permeability was reversed in CIA mice exposed to high amounts of Zonulin [163]. Similarly, Zonulin plays a similar role in SpA [173, 174]. In general, changes in intestinal permeability led to inflammation of microbial secretions and immune cells, which promotes inflammation of surrounding tissues and organs, indicating that improving the TJs and permeability of the gastrointestinal tract may help alleviate the development of systemic inflammatory arthritis.

Fig. 7.

Intestinal barrier and tight junction

The intestinal epithelial cell layer maintains its impermeability to pathogens and toxins through complete tight junctions (TJs). TJs proteins are located at the junction of the parietal mode and the lateral membrane of intestinal epithelial cells and are mainly composed of some transmembrane proteins, such as Occludin, Claudins, and JAMs. These transmembrane proteins can interact with the surface proteins of adjacent cells, and these interactions may be homologous, such as Claudin-1 and Claudin-1; or heterologous such as Claudin-3 and Claudin-1.

Probiotics can improve the intestinal environment and maintain normal barrier function. Bif. pseudocatenulatum CCFM680 and MY40C can protect the intestinal mucus layer and reduce apoptosis of colonic epithelial cells by maintaining intestinal mechanical barrier [175]. Lact. plantarum Y44 can improve oxidative stress and intestinal barrier permeability induced by D-galactose [176] and Lact. acidophilus XY27 can attenuate inflammation and repair intestinal barrier in mice with colitis induced by DSS [177]. In addition, the improvement of intestinal barriers by probiotics was linked to the development of arthritis [146]; both the small intestine of CIA rats treated with Bif. adolescentis mixture and the small intestine of CIA rats showed a significant increase in ZO-1 and Occludin, indicating that probiotics can improve arthritis-related symptoms by improving the intestinal barrier. Although many studies reported the relationship between probiotics and the improvement of the intestinal barrier, most of them focused on inflammatory bowel disease, and very few studies involved systemic inflammatory arthritis. However, it was believed that the improvement of the intestinal barrier and the expression of TJs protein may be a potential target for probiotics to alleviate systemic inflammatory arthritis.

Probiotics affect the composition of immune cells

The disorder of immune cells is an important factor in inducing systemic inflammatory arthritis, while probiotics can regulate the composition of immune cells. The effects of heat-inactivated Lact. reuteri MM2-3 on CIA mice were explored [178], in which heat-inactivated Lact. reuteri MM2-3 could increase the percentage of Treg and CD4⁺IL-10⁺ cells in joint drainage, CD103⁺ dendritic cells in mesenteric lymph nodes, and α4β7⁺Treg cells in the spleen. This means that heat-inactivated probiotics can affect the migration of Treg cells to peripheral tissue in CIA mice, thus reducing inflammation and Lact. sakei can inhibit the development of collagen-induced arthritis by regulating the differentiation of Th17 cells and Breg cells [179]. Another report showed that after intraperitoneal inoculation of Lact. helveticus SBT2171, the concentrated B cells in lymph nodes, germinal center B cells, and CD4 + T cells decreased significantly, thus inhibiting the development of inflammation in CIA mice [180]. From these results, both live bacteria and some heat-inactivated bacteria can regulate the ratio of immune cells and reduce joint inflammation. In recent years, some probiotics have been shown to exhibit health-associated functions based on their metabolites, or lysates, and these substances are named as “Postbiotics” or “Paraprobiotics” [181]. It was also found that postbiotics extracellular polysaccharides of Lact. rhamnosus KL37 can inhibit T cell-dependent immune response in mice, thus improving the development of arthritis [182]. In the future, research on the regulation of immunity by postbiotics may be performed to develop assisted therapy.

Probiotics can indirectly regulate the composition of immune cells by changing the gut microbiota. Intestinal microorganisms have been in a state of dynamic equilibrium in normal and healthy individuals. Antigen-presenting cells, including T cells, can sense the composition of microorganisms through Toll-like receptors to balance the pro-inflammatory and anti-inflammatory balance of local or systemic tissue [183]. When intestinal microbes are affected by genetic, environmental, and/ or other factors, the relative abundance of some harmful bacteria will increase, such as Prevotella and Kleb. pneumoniae. These bacteria activate the immune cells and release pro-inflammatory cytokines to induce inflammation. On the other hand, the intake of probiotics can compete with these harmful bacteria for the inherent living space, thus reducing the proportion of harmful bacteria and making the disordered immune cells to be balanced.

Probiotics can regulate host DNA and RNA methylation.

At the moment, methylation research in systemic inflammatory arthritis is primarily focused on RA. DNA methylation is an important epigenetic modification that participates in the regulation of gene expression and transcriptional splicing. Methylation changes in MHC coding areas may be associated with the risk of RA after a genome-wide methylation study based on 354 RA patients and 337 healthy controls [184]. The changes in DNA methylation of some genes can be detected in the early stage of RA and relatively high levels of DNA methylation were observed at the gene level of the Treg-specific demethylation region (TSDR) in early RA patients [185]. Another report showed that differential methylation of FLS in RA patients may occur in the early stage of RA and changes with the progression of the disease [186]. Current evidence suggests that intestinal microbes regulate DNA methylation. For instance, Bif. breve and Lact. rhamnosus LGG were shown to restore DNA methylation in T84 cells reduced by LPS [187]. Previous literature has showed that the DNA methylation in the 5’ region of the TLR4 gene in intestinal epithelial cells is significantly higher than that in splenocytes in vivo [188]. In addition, the methylation level of TLR4 in the epithelial cells of the large intestine in conventional mice was higher than that in sterile (germ-free) mice [188]. This means that gut microbiota affects the DNA methylation modification of the host in the intestinal tract.

Epigenetic modification of DNA mainly plays a role at the transcriptional level, while reversible RNA methylation mainly regulates gene expression at the post-transcriptional level. Similar to DNA methylation, gut microbiota can also regulate host RNA methylation modification, affect the processing and synthesis of RNA, and then affect protein expression and the process of arthritis. M6A is the most abundant methylation modification on mRNA. The m6A modification level of the transcript is dynamically regulated by a methyltransferase (writers), binding protein (readers/effectors), and demethylase (erasers) [189]. Some studies have shown that reducing the expression of ALKBH5, YTHDF2, and FTO in peripheral blood can reduce the incidence of RA [190]. The effects of m6A methylation and related mRNA expression in MH7A cells were explored [191] and the results showed that m6A is related to the occurrence and development of RA to some extent. A recent study revealed that gut microbiota affected m6A in the cecum and liver of mice, especially in the absence of microbiota, while methyltransferase Mettl16 was significantly downregulated [192]. In addition, Acetobacter mucus and Lact. plantarum were confirmed to play an important role in cecal and liver host m6A modification, cell growth, proliferation, and apoptosis. The study of RNA and DNA methylation on systemic inflammatory arthritis affected by microbiota is still in its infancy, but it will be a potential research aspect.

Probiotics and gut microbiota regulate the expression of RNA in the non-coding region

The RNA in the non-coding region accounts for approximately 70% of the human genome. At present, numerous studies have shown that RNA in the non-coding region can regulate the progression of systemic inflammatory arthritis [193], and these non-coding region RNA mainly include microRNA (miRNA), long non-coding RNA (lncRNA), and circular RNA (circRNA). There were similar characteristics of miRNA changes in rheumatoid arthritis and high-risk individuals; miR-126-3p, let-7d-5p, miR-431-3p, miR-221-3p, miR-24-3p, and miR-130a-3p were significantly higher than those in healthy subjects [194]. Moreover, the downstream targets of these abnormal miRNA were identified and found that they were related to the expression of genes such as NF-κB, STAT1, and STAT3, and the release of pro-inflammatory cytokines and the increased expression of miR-941 in CD14 + cells from PsA patients can enhance the activation and bone resorption activity of osteoclasts by inhibiting the expression of Wnt16 [195]. MiR-10b-5p can be used as a Th17 cellular immune regulatory factor, which exists in Th17 cells of AS patients [196]. LncRNA NEAT1 contained in exosomes produced by peripheral blood monocytes can enhance FLS cell proliferation and release of inflammatory factors via MDM2/SIRT6 [197] and the relationship between ciRS-7, miR-7, and miR-671 was explored and it was found that down-regulated miR-671 may affect ciRS-7 levels in RA patients, while enhanced ciRS-7 may inhibit the function of miR-7 and further alleviate the inhibitory effect of miR-7 on downstream genes of mTOR pathway [198]. The expression of RNA in the non-coding region can regulate the progression of systemic inflammatory arthritis, while probiotics and gut microbiota can regulate the expression of non-coding RNA. Lact. fermentum can improve the expression of miR-150 and miR-143 in the gastrointestinal tract to maintain the homeostasis of the intestinal barrier [199]. Similarly, Lact. casei LC01 can improve the expression of Occludin and ZO-1 by down-regulating miR-144, thus regulating intestinal permeability of intestinal epithelial cells [200]. In fact, oxidative stress, fatty acid changes, and methylation mentioned above are all involved in the non-coding region RNA. Therefore, in the future, exploring competitive endogenous RNA (ceRNA) network [201] and establishing a probiotic-ceRNA-mRNA regulation mechanism will have a good prospect and prospect for the application of microbiota in the treatment of systemic inflammatory arthritis.

Probiotics can relieve inflammation through 5-hydroxytryptamine and its derivative metabolites

Approximately 90% of 5-hydroxytryptamine (5-HT) in humans is produced by intestinal pheochromocytoma cells and regulated by gut microbiota. Previous studies have shown that Bif. breve CCFM1025 can restore the intestinal microecological abnormalities and increase the production of intestinal SCFAs and 5-hydroxytryptophan (5-HTP) biosynthesis in chronically stressed mice. 5-HTP can enter the brain through the blood–brain barrier to produce 5-HT [202]. At present, there are two main views on the effect of 5-HT regulated by gut microbiota on arthritis. (1) 5-HT regulated by gut microbiota is involved in the inhibition of pain. The content of 5-HT was decreased in the dorsal raphe nucleus by injection of a 5-HT antibody and showed higher pain index and significant pain response in pain test [203]. This view is mainly from the brain-gut-joint axis, and the increase of 5-HT will weaken the pain effect caused by arthritis, to achieve the purpose of relief. (2) An increase in the level of 5-hydroxy-indole-3-acetic acid (5-HIAA), a derivative of 5-HT, can activate the aromatic hydrocarbon receptor (AhR) and inhibit Breg-dependent arthritis [12]. This point of view advocates that the effects of 5-HT and its derivatives on arthritis should be explained from intestinal-transmitter-immune cells. Whilst the specific mechanism through which 5-HT plays its role is still in the hypothetical stage, this warrants further investigation.

Fecal microbiota transplantation and quorum sensing

Over 60 years have passed since fecal microbiota transplantation (FMT) was first used as a microbiota-assisted therapy [204]. FMT has been developed to be a colorless and odorless treatment method for patients in a medical setting [205]. Patients, however, are less likely to accept FMT than probiotics due to their limited understanding of the gut microbiota. FMT is mainly used to treat relapsed or refractory C. difficile infections, with a cure rate of 90% [206]. Additionally, FMT has been extended to the adjuvant treatment of inflammatory bowel disease, irritable bowel syndrome, tumors, type I diabetes, and other diseases. The greatest distinction between FMT and probiotics in terms of mechanism is that FMT can induce a condition of quorum sensing, which causes the recipient's gut microbiota to return to normal and alleviate sickness. According to conventional wisdom, bacteria are one of the major factors in FMT. But recent research has demonstrated that FMT transfers not only bacteria but also phages, fibers, mucus, colon cells, proteins, lipids, bile acids, SCFAs, and other elements found in donor feces [205]. Together, these elements create a bacterial microenvironment that leads to the normalization of the patient’s aberrant gut microbiota. Currently, FMT research on systemic inflammatory arthritis is in its early stages, with only a few cases published. The first case report of FMT in RA was published in 2020 [207]. A 20-year-old woman with RA for 5 years was the patient. Her arthritic symptoms were greatly reduced after six weeks of FMT. The rheumatoid factor titer decreased from 314 to 158 IU/mL, the Disease Activity Score 28 (DAS 28) score dropped from 6.6 to 1.9, and she experienced no negative side effects. This means that FMT may help reduce or stop the inflammatory response in RA and aid in the restoration of healthy gut microbiota. Another study investigated the safety and effectiveness of a 26-week FMT in PsA patients [208]. In the trial, there were 31 PsA patients altogether, 15 of whom were assigned to the FMT group. Although there were no major side effects during their clinical evaluation, the data showed that FMT was less effective than the sham group at treating active peripheral PsA. FMT appears to be safe for assisted therapy of systemic inflammatory arthritis based on current findings, but efficacy research needs to be conducted. Moreover, the optimal dose of FMT, the difference between donor and recipient relationship, the frequency of performing FMT, and other issues still need many clinical cases to verify and answer. The use of FMT in systemic inflammatory arthritis has enormous potential. Future FMT advancements may lead to the creation of a full system of artificial fecal bacteria culture, component combination, and transplantation to prevent the spread of infectious agents that could be present in feces and enhance its use as assisted therapy for systemic inflammatory arthritis.

Conclusion and prospects

In this review, we discussed rheumatoid arthritis, ankylosing spondylitis, and psoriatic arthritis, which account for the largest proportion of patients with systemic inflammatory arthritis. From the defects of clinical treatment of systemic inflammatory arthritis to the possibility that microbiota can be used as evidence for the identification of systemic inflammatory arthritis, and then to the possibility of microbiota improving the mechanistic of systemic inflammatory arthritis insights, the possibility of microbiota in the treatment of systemic inflammatory arthritis was discussed. The change of microbiota helps find the hidden danger of systemic inflammatory arthritis and helps patients reduce their dependence on drugs with associated side effects. However, at present, for the microbiota-assisted therapy of systemic inflammatory arthritis, there is still a lack of ability to detect and determine specific markers of pathogenic bacteria, and part of the treatment mechanism is not clear. Therefore, this review points out the further aspects which need to be explored. With the rise of medical care and the continuous development of microbiome technology, these undiscovered areas will eventually become clear, and microbiota-assisted therapy will be a promising application in the future.

Supplementary Information

Below is the link to the electronic supplementary material.

Author contributions

WC and BY supervised the study. RPR, CS and HZ participated in the design and discussion of the research. BL, BY, XL, JZ, RPR, CS, HZ, and WC contributed to the analysis, and interpretation for the work. BL drafted manuscript. BY, RPR and WC revised the manuscript and all authors have read and approved final interpretation for the work.

Funding

This research was supported by the National Natural Science Foundation of China (Nos. 32021005, 31820103010), and the Collaborative Innovation Center of Food Safety and Quality Control in Jiangsu Province.

Availability of data and material

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

Declarations

Conflict of interest

The authors declare no conflict of interest.

Ethical approval and consent to participate

Not applicable.

Consent for publication

The manuscript does not contain human research, and any individual person’s data in any form (including any individual details, images or videos).